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Science, Math and Medicine – Working Together To Understand the Diagnosis, Classification and Treatment of Port-Wine Stains.

Martin Mihm, Jr. MD; Linda Rozell-Shannon, M.S.

To the naked eye, some birthmarks look as though someone had permanently
stained the skin with wine, thus the term “port-wine stain.” It
has been documented (Mulliken, 1988) that from the early eighteenth
century until World War II, more port wine was consumed in England
than any other wine. Because of the wine’s popularity, English
novelists and medical writers of that time period used the term
“port-wine stain” to describe a crimson colored vascular birthmark.
To this day, the term “port-wine stain” is used to describe a specific
type of vascular birthmark. The Latin term for this type of birthmark
is naevus flammeus. Folklore hints at a superstition that the mother
had a craving for port wine and that is why the infant is “stained”.

Aside from folklore, the port-wine stain has also been the subject
of great confusion with another type of vascular birthmark that
was once called a “capillary hemangioma” and now is more accurately
known as a “hemangioma.” Unlike the port-wine stain, the hemangioma
is a tumor of infants that fades or involutes over a period of years.
Over time and as diagnostic skills have improved, the port-wine
stain became known as a “capillary malformation” and has recently
been revised to a more accurate classification of “venular/capillary
malformation” through the use of histologic and immunophenotypic
criteria. Prior to the use of modern immunophenotypic screening
and histologic profiling, physicians relied on clinical presentation
to diagnose and classify vascular birthmark types. Some biology
was also used to segregate the hemangioma from the malformation,
with a port-wine stain being a type of malformation. This type
of biologic classification (Mulliken and Young 1988) that differentiated
a cellular-hyerplasia (hemangiomas) from a cellular hypertrophy
(malformations) was the beginning of establishing a more scientific
basis for understanding and classifying vascular birthmarks. With
this in mind, the objective of this paper is to educate its readers
regarding the role of histopathology and immunophenotypic staining
in understanding the diagnosis and classification of port-wine stains,
as well as the role nerve innervation plays in the progression and
treatment of these vascular birthmarks. The understanding of the
histology and innervation of these lesions is critical in ascribing
the proper laser settings to insure the best “clearance” of the
port wine stain. Additionally, this paper summarizes a new mathematical
approach that is being used to determine the optimal laser wavelength
for treating port wine stains.

Histopathology of port-wine stains as used to diagnose and
differentiate these lesions from other common vascular tumors

Port-wine stains are congenital birthmarks characterized histologically
by ecstatic vessels of capillary or venular type within the papillary
and reticular dermis. In some cases they extend into the superficial
subcutaneous tissues. They are non-proliferative lesions that do
not involute and are therefore better known as a type of vascular
malformation, rather than a hemangioma.

In the past, port-wine stains have been lumped together with very
common vascular birthmarks known as salmon patches, stork bites
or angel kisses. However, port-wine stains are different from these
common vascular birthmarks in a number of important aspects. Salmon
patches are common in newborns; occur as pink macules, most commonly
on the nape of the neck, eyelids and glabella and often fade or
disappear with time. The color of these macular stains may deepen
with exercise or emotional upset. These lesions thus may represent
focal areas of physiologic vascular dysfunction. On the other hand,
port-wine stains are relatively rare macular lesions (occurring
in about 0.3% of newborns) and generally appear on the skin of the
head and neck within the distribution of the trigeminal nerve.
They persist throughout life and may become raised, nodular, or
darken with age. Port-wine stains may also be associated with ipsilateral
leptomenigeal and choroids venous malformations (Sturge-Weber Syndrome).
Port-wine like stains may sometimes directly overlie deeper malformations
of large vessel type in other regions of the body, as in association
with Klippel-Trenaunay Syndrome and Parkes-Weber Syndrome. These
latter lesions are histologically distinct, however, from true port-wine
stains. The establishment of this molecular biological basis for
stain classifications is probably the most significant effort toward
understanding these lesions in decades.

Immunophenotypic criteria of port-wine stains

Biopsies of port-wine stains from infants and young children may
not reveal the characteristic vessel ectasia, which does not begin
to become prominent until about 10 years of age (Finley 1984).
From that time onward, capillary and venule-size vessels in the
upper dermis become progressively dilated and filled with erythrocytes.
These vessels are lined by flat, inactive-appearing endothelia,
without evidence of mitotic activity. While there is some controversy
as to whether dermal vessels are actually increased in number in
port-wine stains compared with normal skin (Barsky 1980; Smoller
and Rosen, 1986) there is no evidence that the number of vessels
in these lesions changes with aging. What we do know is that ectasia
begins superficially within the lesion and progressively involves
deeper vessels, eventually extending into the reticular dermis and
focally into the subcutaneous tissue. Immunoreactions for vWf,
collagenous basement membrane proteins, and fibronectin have not
shown differences between port-wine stains and normal skin (Finley
1982). However, immunoreaction for S-100, a protein found in Schwann
cells, reveals a significant decrease in perivascular nerve density
in port-wine stains, suggesting that inadequate innervation may
be responsible for the progressive vascular dilation that is characteristic
of the lesion (Smoller and Rosen 1986).

This progression may also explain the nodular clinical appearance
that develops mostly in older patients, and is called “cobbling”.

The Sick Dermatome Theory

In 1986 Smoller and Rosen postulated that an altered or even absent
neural modulation of the vascular plexus was responsible for the
progressive ectasia that occurs with the advancing age of the port-wine
stain. An analysis of biopsy specimens from both normal skin and
port-wine stained skin showed no difference in vessel number. There
was, however, a marked increase in the perivascular nerve density
in port-wine stained biopsy specimens. Rydy (1990) demonstrated
a decrease in both sympathetic and sensory innervation of the papillary
plexus. Because sensory fibers elaborate several neuropeptides,
including substance P, which is known to stimulate smooth muscle
growth and calcitonin gene-related peptide (which stimulates endothelial
cell growth), they postulated an absence of trophic effects as a
possible cause (Nilsson 1985; Haegerstrand 1990). In light of all
of these findings, the “sick dermatome” theory was postulated (Waner
and Suen 1999) to explain the etiology of port-wine stains. Waner/Suen
theorized that a port-wine stain is a manifestation of a “sick dermatome”
in which there is an absolute or relative deficiency of vascular
autonomic and sensory vascular innervation as the underlying pathology.
Lesions with an absolute deficiency will progress more rapidly and
early hypertrophy with cobblestone formation is likely, whereas
a relative deficient of autonomic innervations will give rise to
a slower progression.

Classification and Treatment Parameters

Within the papillary vascular plexus, video microscopy has revealed
three patterns of vascular ectasia (Motly 1996); type 1,
ectasia of the vertical loops of the papillary plexus; type
2, ectasia of the deeper, horizontal vessels in the papillary
plexus; and type 3, mixed pattern with varying degrees
of vertical and horizontal vascular ectasia. Recognition of these
patterns is important in that they impact on the response to laser
treatment. Given that laser light has a limited depth of penetration,
type 1 lesions are more apt to respond well to treatment
and type 3 lesions are likely to respond poorly (Waner/Suen
1999).

Because there is so much variability in the appearance of port-wine
stains, it becomes essential to classify these lesions. Earlier
attempts at classification relied on color and used paint color
charts. These were found to be unreliable because it was difficult
to match flesh tones with the colors used to paint the interior
of a building. Therefore, this was not an appropriate way of classifying
port-wine stains. Further, the color of a lesion is determined
by the degree of oxygenation of the hemoglobin, which is dependent
on the degree of perfusion of the vascular bed, which in turn depends
on a number of factors such as ambient temperature, the level of
circulating catecholamines and local metabolites. We now classify
port-wine stains in accordance with their degree of vascular ectasia
because this is the true cause of the variation in clinical appearance.
This classification recognizes four grades of ectasia, Grades
I to IV.Grade I represents the smallest vessels and
Grade IV the largest. When using this classification, one
should always bear in mind that there is a progression between the
grades and that the division between grade are, to a large extent,
arbitrary. The main purpose of this new classification is to assign
a grade for ease in communication and determination of the appropriate
laser treatment settings.

Grade I lesions are the earliest lesions and thus have
the smallest vessels (50-80 um in diameter). Using x6 magnification
and transillumination, individual vessels can only just be discerned
and appear like grains of sand. Clinically, these lesions are light
or dark pink macules. Grade II lesions are more advanced
(vessel diameter = 80-120 um). Individual vessels are clearly visible
to the naked eye, especially in less dense areas. They are thus
clearly distinguishable macules. Grade III lesions are more
ecstatic (120-150 um). By this stage, the space between the vessels
has been replaced by the dilated vessels. Individual vessels may
still be visible on the edges of the lesion or in a less dense lesion,
but by and large individual vessels are no longer visible. The
lesion is usually thick, purple, and palpable. Eventually, dilated
vessels will coalesce to form nodules, otherwise known as cobblestones.

Treatment Enhanced By New Mathematical Model

Various mathematical models have been developed to predict optimal
laser parameters to achieve high-efficacy laser treatment of port-wine
stains.

A recent study was done using a numerical method to use the diffusion
approximation to model photothermal effects in a heterogeneous medium
to study the laser treatment of PWS. The thermal field within the
specific vessels was calculated with spatial resolution of sub micrometer
for small vessels and of a few micrometers for large vessels with
temporal resolution of microseconds. The model used allowed the
study of coagulation patterns within specific blood vessels and
was able to explain histopathologic observations reported for laser
treatments of PWS. These included partial coagulation in vessels
of 200 um and up in diameter and the sparing of small vessels (10
um). It also indicated that partial coagulation might lead to insufficient
vessel destruction, which could result in vessel repair over time.
This is also significant in that it may explain the very controversial
theory that some port wine stains reappear. The prediction of the
sparing of small vessels is the premise for the effective laser
treatment of PWS in which dilated vessels (50-150 um) are damaged
and capillaries remain intact to continue to supply blood to the
treated region. The model was combined with histopathology and
supports the theory that the diffusion approximation is valid for
modeling photothermal interactions in the laser treatment of PWS
with FPDL (flashlamp-pumped dye laser) at the 585 and the 595 nm
wavelengths.

Summary

Current clinical diagnosis combined with histologic and immunophenotypic
criteria has become key to the pathological diagnosis and proper
classification of vascular birthmarks. The new classification and
port-wine stain grading criteria, combined with the more in-depth
understanding of the “sick dermatome” theory have assisted us in
our study of these hyper vascular birthmarks. The combination of
good clinical evaluation supported by histologic and immunophenotypic
criteria, and this new scientific understanding, will assist the
treating physician in prescribing the use of laser therapy to oblate
the appearance of the port-wine stain. Additionally, the recent
application of mathematical modeling to understand vessel depth
and laser wavelength settings and absorption rates will insure optimal
use of the laser to treat the port-wine stain most effectively.

As we continue to learn more and more about such vascular birthmarks
as port-wine stains, we realize that they are truly multi-disciplinary
and as such, require physicians and scientists from multiple disciplines
to work closely together to understand the histopathology and progression
of these lesions in order to prescribe the most effective treatment.
This is a new beginning for the fields of math, science and medicine
to work together to diagnose, classify and prescribe treatment for
a very complicated and often problematic birth defect…the port-wine
stain.

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